First in Human Experience with Peritoneal Direct Sodium Removal Using a Zero Sodium Solution: A New Candidate Therapy for Volume Overload

Abstract

Background: Loop diuretics have well described toxicities and loss of response to these agents is common. Alternative strategies are needed for the maintenance of euvolemia in heart failure (HF). Non-renal removal of sodium directly across the peritoneal membrane (direct sodium removal, DSR) using a sodium free osmotic solution should result in extraction of large quantities of sodium with limited off target solute removal.

Methods: This report describes the pre-clinical development and first-in-human proof of concept for DSR. Sodium free 10% dextrose was utilized as the DSR solution. Porcine experiments were conducted to investigate the optimal dwell time, safety, scalability, and to determine the effect of experimental HF. In the human study, participants with end stage renal disease (ESRD) on peritoneal dialysis (PD) underwent randomization and crossover to either a two-hour dwell with one liter of DSR solution or standard PD solution (Dianeal 4.25% dextrose, Baxter). The primary endpoint was completion of the 2-hour dwell without significant discomfort or adverse events, and the secondary endpoint was difference in sodium removal between DSR and standard PD solution.

Results: Porcine experiments revealed that one liter of DSR solution removed 4.1±0.4 grams of sodium in 2 hours with negligible off target solute removal and overall stable serum electrolytes. Increasing the volume of DSR solution cycled across the peritoneum increased sodium removal and substantially decreased plasma volume (p=0.005). In the setting of experimental HF with elevated right atrial pressure, sodium removal was ~4 times greater than in healthy animals (p<0.001). In the human proof of concept study, DSR solution was well-tolerated and not associated with significant discomfort or adverse events. Plasma electrolyte concentrations were stable and off target solute removal was negligible. Sodium removal was substantially higher with DSR (4.5±0.4 grams) compared to standard PD solution (1.0±0.3 grams, p<0.0001).

Conclusions: DSR was well-tolerated in both animals and human subjects and produced substantially greater sodium removal than standard PD solution. Additional research evaluating the use of DSR as a method to prevent and treat hypervolemia in HF is warranted.

Clinical Trial Registration: URL: https://clinicaltrials.gov Unique identifier: NCT03801226